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Once activated, the C1s enzyme acts on the next two components of the classical pathway, cleaving C4 and then C2 to generate two large fragments, C4b and C2b,which together form the C3 convertase of the classical pathway. In the firststep, C1s cleaves C4 to produce C4b, which binds covalently to the surface ofthe pathogen. The covalently attached C4b then binds one molecule of C2, makingit susceptible, in turn, to cleavage by C1s. C1s cleaves C2 to produce the largefragment C2b, which is itself a serine protease. The complex of C4b with theactive serine protease C2b remains on the surface of the pathogen as the C3convertase of the classical pathway. Its most important activity is to cleavelarge numbers of C3 molecules to produce C3b molecules that coat the pathogensurface. At the same time, the other cleavage product, C3a, initiates a localinflammatory response. These reactions, which comprise the classical pathway ofcomplement activation, are shown in schematic form in Fig. 2.11; the proteins involved, and their active forms,are listed in Fig. 2.12.

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The C3 convertases resulting from activation of the classical and MB-lectinpathways (C4b,2b) and from the alternative pathway (C3b,Bb) are apparentlydistinct. However, understanding of the complement system is simplified somewhatby recognition of the close evolutionary relationships between the differentcomplement proteins. Thus the complement zymogens, factor B and C2, are closelyrelated proteins encoded by homologous genes located in tandem in the major histocompatibility complex (MHC) on human chromosome 6. Furthermore, theirrespective binding partners, C3 and C4, both contain thioester bonds thatprovide the means of covalently attaching the C3 convertases to a pathogensurface. Only one component of the alternative pathway appears entirelyunrelated to its functional equivalents in the classical and MB-lectin pathways;this is the initiating serine protease, factor D. Factor D can also be singledout as the only activating protease of the complement system to circulate as anactive enzyme rather than a zymogen. This is both necessary for the initiationof the alternative pathway through spontaneous C3 cleavage, and safe for thehost because factor D has no other substrate than factor B when bound to C3b.This means that factor D only finds its substrate at a very low level in plasma,and at pathogen surfaces where the alternative pathway of complement activationis allowed to proceed.

In addition to the mechanisms for preventing C3 convertase formation and C4 andC3 deposition on cell membranes, there are also inhibitory mechanisms thatprevent the inappropriate insertion of the membrane-attack complex intomembranes. We saw in Section 2-13 thatthe membrane-attack complex polymerizes onto C5b molecules released from C5convertase. This complex mainly inserts into cell membranes adjacent to the siteof the C5 convertase, that is, close to the site of complement activation on apathogen. However, some newly formed membrane-attack complexes may diffuse fromthe site of complement activation and insert into adjacent host cell membranes.Several plasma proteins bind to the C5b,6,7 complex and thereby inhibit itsrandom insertion into cell membranes. The most important is probably C8β itself,when it binds to C5b,6,7 in the fluid phase. Host cell membranes also contain anintrinsic protein, CD59 or protectin, which inhibits the bindingof C9 to the C5b,6,7,8 complex (see Fig.2.26, bottom row). CD59 and DAF are both linked to the cell surfaceby a phosphoinositol glycolipid (PIG) tail, like many other membrane proteins.One of the enzymes involved in the synthesis of PIG tails is encoded onchromosome X. In people with a somatic mutation in this gene in a clone ofhematopoietic cells, both CD59 and DAF fail to function. This causes the diseaseparoxysmal nocturnalhemoglobinuria, which is characterized by episodes of intravascularred blood cell lysis by complement. Red blood cells that lack CD59 only are alsosusceptible to destruction as a result of spontaneous activation of thecomplement cascade. 076b4e4f54